Acquired resistance is a fundamental problem limiting the efficacy of tyrosine kinase inhibitors (TKIs) in EGFR mutant NSCLC. In over half of the cases of acquired resistance to the first generation inhibitors gefitinib and erlotinib, a secondary mutation to EGFR, T790M, promotes resistance by preventing these drugs from fully suppressing the receptor. The recent development of next generation EGFR TKIs has proven to be a major breakthrough in the treatment of these patients. In clinical trials testing the third generation EGFR inhibitors CO-1686 and AZD9291, response rates of greater than 50% in T790M+ patients have been reported. While these drugs hold a great deal of promise, they too will be limited, initially by intrinsic resistance, and eventually by acquired resistance. To study intrinsic resistance in this setting, we have developed a panel of cell lines derived from biopsies of T790M+ erlotinib-resistant patients, tested their sensitivity to third generation inhibitors and identified biomarkers that predict a lack of response. To study acquired resistance, we have generated resistance in these cells lines in vitro and derived additional models directly from patient biopsies following progression on the clinical trial. Using a combination of functional, sequencing, and drug screening approaches we have begun to identify resistance mechanisms to third generation inhibitors.

Citation Format: Matt J. Niederst. Mechanisms of intrinsic and acquired resistance to third generation inhibitors in EGFR mutant NSCLC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 685. doi:10.1158/1538-7445.AM2015-685